MicroRNA therapeutics: design of single-stranded miR-216b mimics to target <i>KRAS</i> in pancreatic cancer cells

Ferino, Annalisa; Miglietta, Giulia; Picco, Raffaella; Vogel, Stefan; Wengel, Jesper; Xodo, Luigi E.

doi:10.1080/15476286.2018.1526536

Cited by 31 publications

(24 citation statements)

References 54 publications

(90 reference statements)

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“…ss-miR mimics might combine the power of function through the RNAi pathway with the more favorable pharmacological properties of single-stranded oligonucleotides 13–15 . Plant miRs have a naturally occurring 2′- O -methyl group that confers high stability to RNA oligonucleotides without affecting their biological activities 33 .…”

Section: Resultsmentioning

confidence: 99%

“…The mechanisms of action of microRNAs (miRs) have led to their suggestions for therapeutic applications in analogy with exogenously supplemented small interfering RNAs (siRNAs), which induce degradation of sequence-specific homologous mRNAs via RNA interference (RNAi). Single-stranded miRs (ss-miR) containing the seed sequence mimics the ability of duplex miRs in inhibiting the expression of target genes 13–15 and the chemical modification with 2′- O -methyl at 3′-end increases their stability in vivo and does not affect their biological activity 16 . Notably, 2′- O -methyl modification is a peculiarity of plant miRs 17 .…”

Section: Introductionmentioning

confidence: 99%

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Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts

et al. 2019

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There is a growing interest in therapeutically targeting the inflammatory response that underlies age-related chronic diseases including obesity and type 2 diabetes. Through integrative small RNA sequencing, we show the presence of conserved plant miR159a and miR156c in dried nuts having high complementarity with the mammalian TNF receptor superfamily member 1a (Tnfrsf1a) transcript. We detected both miR159a and miR156c in exosome-like nut nanovesicles (NVs) and demonstrated that such NVs reduce Tnfrsf1a protein and dampen TNF-α signaling pathway in adipocytes. Synthetic single-stranded microRNAs (ss-miRs) modified with 2′- O -methyl group function as miR mimics. In plants, this modification naturally occurs on nearly all small RNAs. 2′- O -methylated ss-miR mimics for miR156c and miR159a decreased Tnfrsf1a protein and inflammatory markers in hypertrophic as well as TNF-α-treated adipocytes and macrophages. miR156c and miR159a mimics effectively suppress inflammation in mice, highlighting a potential role of plant miR-based, single-stranded oligonucleotides in treating inflammatory-associated metabolic diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts

et al. 2019

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“…Moreover, it is well described that miR-216b targets K-RAS in many cell types. It has been documented in pancreatic 39,40 , nasopharyngeal 41 and renal tumors 42 that decreasing the abundance of the K-RAS gene consequently leads to low cellular proliferation and differentiation. Thus, we propose that lower levels of K-RAS in LF two-cell embryos is a temporal effect resulting from the higher level of miR-216b in LF zygotes provided by LF sperm cells.…”

Section: Discussionmentioning

confidence: 99%

Sperm-borne miR-216b modulates cell proliferation during early embryo development via K-RAS

Alves

Arruda

et al. 2019

Sci Rep

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Semen fertilizing potential is dependent upon the morphological, functional and molecular attributes of sperm. Sperm microRNAs (miRNAs) were recently shown to hold promise regarding their association with different fertility phenotypes. However, their role in fertility regulation remains to be determined. We postulated that sperm miRNAs might regulate early embryonic development. From this perspective, sperm quality and 380 sperm miRNAs were investigated in frozen–thawed semen from high (HF; 54.3 ± 1.0% pregnancy rate) and low (LF; 41.5 ± 2.3%) fertility bulls. Out of nine miRNAs that showed different levels in sperm cells, miR-216b was present at lower levels in HF sperm cells and zygotes. Among miR-216b target genes ( K-RAS , BECN1 and JUN ), K-RAS , related to cell proliferation, revealed a higher level in HF two-cell embryos. First cleavage rate, blastocyst cell number and division number were also higher in HF. In addition, by using a model based on polyspermy embryos, we demonstrated an increase in miR-216b levels in zygotes associated with sperm cell entry. Our results shed light on a possible mechanism of paternal contribution involving sperm-borne miR-216b that modulates levels of miR-216b in zygotes and K-RAS in two-cell embryos. This modulation might regulate early development by interfering with the first cleavage and blastocyst quality.

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“…The success and advantages of LNA-containing oligomers for diverse applications stimulated the search for similar compounds, improving their properties. Many derivatives were recently introduced, like BNA NC with different substitutions at the N atom (of which a methyl group is the most commonly used to date) (Figure 1) [87], 2′- O ,4′- C -ethylene-bridged nucleic acid (ENA) [88], 2′- O ,4′- C -methylenoxymethylene-bridged nucleic acid [89], or unlocked nucleic acids (UNA) [90,91]. The bridge in the different BNA compounds can have a different number of members in the ring, the most widely used to date being BNA NC , a six-member ring [30,31].…”

Section: Bnancmentioning

confidence: 99%

Bridged Nucleic Acids Reloaded

2019

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Oligonucleotides are key compounds widely used for research, diagnostics, and therapeutics. The rapid increase in oligonucleotide-based applications, together with the progress in nucleic acids research, has led to the design of nucleotide analogs that, when part of these oligomers, enhance their efficiency, bioavailability, or stability. One of the most useful nucleotide analogs is the first-generation bridged nucleic acids (BNA), also known as locked nucleic acids (LNA), which were used in combination with ribonucleotides, deoxyribonucleotides, or other analogs to construct oligomers with diverse applications. However, there is still room to improve their efficiency, bioavailability, stability, and, importantly, toxicity. A second-generation BNA, BNANC (2′-O,4′-aminoethylene bridged nucleic acid), has been recently made available. Oligomers containing these analogs not only showed less toxicity when compared to LNA-containing compounds but, in some cases, also exhibited higher specificity. Although there are still few applications where BNANC-containing compounds have been researched, the promising results warrant more effort in incorporating these analogs for other applications. Furthermore, newer BNA compounds will be introduced in the near future, offering great hope to oligonucleotide-based fields of research and applications.

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MicroRNA therapeutics: design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells

Cited by 31 publications

References 54 publications

Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts

Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts

Sperm-borne miR-216b modulates cell proliferation during early embryo development via K-RAS

Bridged Nucleic Acids Reloaded

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